Neurobiology of Psychosis Flashcards
Brain changes in schizophrenia?
Reduced frontal lobe volume
Reduced frontal lobe grey matter
Enlarged lateral ventricle volume
Dopamine hypothesis of schizophrenia?
Excess D2
THEREFORE dopamine receptor agonists are used to treat symptoms of schizophrenia
Action of D1 receptor family?
Stimulates cAMP
Action of D2 receptor family?
Inhibits adenylyl cyclase
Inhibits voltage-activated Ca2+ channels
Opens K+ channels
Where are D1 receptors found?
Neostriatum; cerebral cortex. olfactory tubercle, nucleus accumbens
Where are D2 receptors found?
Neostriatum; olfactory tubercle; nucleus accumbens
Where are D3 receptors found?
Nucleus accumbens; island of Calleja
Where are D4 receptors found?
Midbrain; amygdala
Where are D5 receptors found?
Hippocampus
D2 antagonists?
Haloperidol
Atypical antipsychotics
D4 antagonists?
Clozapine
Dopamine relationship to psychosis?
Subcortical dopamine hyperactivity
Dopamine relationship to negative and cognitive symptoms in schizophrenia?
Mesocortical dopamine hypoactivity
What other nTs aparat from dopamine are involved in schizophrenia?
Glutamatergic; altered NMDA receptors
5-HT
What genes are dysregulated in schizophrenia?
Neuregulin (growth and development of brain)
Dysbindin (neuronal plasticity)
DISC-1 (neurite growth)
Examples of typical antipsychotics?
Haloperidol
Chlorpromazine
Action of typical antipsychotics?
D2 antagonism - block post synaptic receptor
Are antipsychotics dose dependent?
Strong correlation between the average dose required to improve clinical symptoms and D2 receptor binding activity
What are atypical antipsychotics?
Less likely to induce EPS
High 5-HT2a to D2 ratio
Better efficacy against negative symptoms
What are the atypical antipsychotics?
Olanzapine Risperidone Quetiapine Clozapine Aripiprazole
Why do antipsychotics result in parkinsonism?
Block D2 receptors in niostriatum
What is acute dystonic reaction?
Muscle spasms
How are acute dystonic reactions treated?
Prochlorperazine
Procyclidine
ACh antagonists
What is akathisia?
Internal restlessness; feeling need to constantly move, fidgeting, wriggling or pacin
What is tardive dyskinesia?
Repetitive involuntary purposeless movements; gramicing, sticking tongue out, lip smacking, pursing lips, blinking
Hyperprolactinemia?
Sexual dysfunction Galactorrhoea Gynaecomastia Amenorrhoea Infertility Lower oestrogen and testerone = osteoporosis
What does 5HT-2 blockade via atypical antipsychotics result in?
Metabolic syndrome
What does antagonism of histamine via atypical antipsychotics result in?
Sedation
Increased appetite
Can reduce nausea and vomiting
What does the antagonism of alpha-1 adrenergic activity via atypical antipsychotics result in?
Hypotension
Interrupts the baroreflex; dizziness, lightheadedness, fainting
Consequences of muscarinic blockade?
Blurred vision Dry mouth Constipation Urinary retention Sedation and confusion
Which antipsychotics are daily dosing?
Olanzapine
Quetiapine
Which antipsychotics will be used in those already with parkinson’s?
Clozapine (weekly FBC for 18 weeks then fortnightly)
Quetiapine
Which antipsychotics are most likely to cause metabolic syndrome?
OLANZAPINE CLOZAPINE Risperidone Quetiapine Aripiprazole These are ordered from worst to least
Which antipsychotics are most likely to cause falls?
Those with alpha adrenergic blockage (clozapine, quetiapine, risperidone)
Those with histamine blockade (Quetiapine, clozapine, olanzapine)
Which antipsychotics are most likely to cause sedation?
Those with histamine blockage; quetiapine, clozapine, olanzapine
Which antipsychotic is least likely to cause a recurrence of parkinsonism?
Clozapine
Quetipapine
What is the side effect caused by haloperidol antagonisms in the pituitary gland?
Sexual dysfunction
When is clozapine prescribed in schizophrenia?
After 2 adequate trials of other antipsychotics
Why is clozapine a scary drug to prescribe?
Agranulocytosis Myocarditis; non specific ST changes Weight gain - up to 20kgs Hyper salivation - treat with hyoscine Cardiomyopathy Pulmonary embolism
Monitoring with clozapine?
Weekly FBC for the first 6 months Fortnightly for next 6 months Every 4 weeks thereafter One month after cessation of clozapine ECG BP HR
What is the pathogenesis behind myocarditis induced by clozapine?
IgE reaction; cytokine release of hypercatecholaminaemia
What does blockage of the D2 receptors in the mesolimbic system result in?
Reduction in positive symptoms such as delusions and hallucinations
What does blockage of the D2 receptors in the mesocortical system (already underactive in schizophrenia) result in?
Worsening of negative symptoms; diminished energy, restriction in emotional and verbal engagement
What does blockage of the D2 receptors in the nigrostriatal system result in?
Extrapyramidal symptoms
Tardive dyskinesia
Parkinsonian symptoms; tremor, muscle rigidity, bradykinesia
What does blockage of the D2 receptors in the tuberoinfundibular system result in?
Increase in blood prolactin levels; amenorrhoea, gynaecomastia, sexual dysfunction
Low-potency typical antipsychotic?
Chlopromazine
High-potency typical antipsychotic?
Haloperidol
Which atypical antipsychotic has the strongest affinity for D2 receptors?
Risperidone; highest potential for EPS and hyperprolactinemia
Main receptors acted on by risperidone?
5-HT2A
Main receptor acted on by olanzapine?
5-HT2A
Main receptor acted on by aripiprazole?
5-HT5A
What are the 2 main receptors acted on by quetiapine?
H1
Alpha
Treatment of acute dystonic reaction?
Acetylcholine antagonists
Procyclidine, prochlorperazine, orhphenadrine
Areas of the brain involved in the mesolimbic dopamine system?
Ventral tegmental area Amygdala Hippocampus Nucleus accumbens Frontal cortex
Antagonism of which receptor can help with the negative symptoms seen in schizophrenia?
Serotonin
